Head and Neck Section, Surgical Oncology Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
Head and Neck Section, Surgical Oncology Program, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
Cancer Cell. 2023 May 8;41(5):887-902.e5. doi: 10.1016/j.ccell.2023.03.014. Epub 2023 Apr 13.
Neoadjuvant immunotherapies (NITs) have led to clinical benefits in several cancers. Characterization of the molecular mechanisms underlying responses to NIT may lead to improved treatment strategies. Here we show that exhausted, tumor-infiltrating CD8 T (Tex) cells display local and systemic responses to concurrent neoadjuvant TGF-β and PD-L1 blockade. NIT induces a significant and selective increase in circulating Tex cells associated with reduced intratumoral expression of the tissue-retention marker CD103. TGF-β-driven CD103 expression on CD8 T cells is reversed following TGF-β neutralization in vitro, implicating TGF-β in T cell tissue retention and impaired systemic immunity. Transcriptional changes implicate T cell receptor signaling and glutamine metabolism as important determinants of enhanced or reduced Tex treatment response, respectively. Our analysis illustrates physiological and metabolic changes underlying T cell responses to NIT, highlighting the interplay between immunosuppression, tissue retention, and systemic anti-tumor immunity and suggest antagonism of T cell tissue retention as a promising neoadjuvant treatment strategy.
新辅助免疫疗法（NIT）已在多种癌症中带来临床获益。对 NIT 反应背后的分子机制进行特征分析可能会导致改进的治疗策略。在这里，我们显示耗竭的肿瘤浸润 CD8 T（Tex）细胞对同时的新辅助 TGF-β和 PD-L1 阻断显示出局部和全身反应。NIT 诱导与肿瘤内组织保留标记物 CD103 表达降低相关的循环 Tex 细胞的显著和选择性增加。TGF-β 中和在体外逆转 TGF-β驱动的 CD8 T 细胞上的 CD103 表达，表明 TGF-β参与 T 细胞组织保留和受损的全身免疫。转录变化表明 T 细胞受体信号和谷氨酰胺代谢分别是增强或降低 Tex 治疗反应的重要决定因素。我们的分析说明了 T 细胞对 NIT 反应的生理和代谢变化，强调了免疫抑制、组织保留和全身抗肿瘤免疫之间的相互作用，并表明拮抗 T 细胞组织保留是一种很有前途的新辅助治疗策略。
